The FDA has forced Cellectis $CLLS to slam the brakes on two clinical trials of its off-the-shelf version of a CAR-T therapy after their first patient was killed by a lethally toxic reaction to treatment.

According to the biotech, which is based in Paris with R&D operations in New York, a 78-year-old patient suffering from blastic plasmacytoid dendritic cell neoplasm (BPDCN) died eight days after receiving the biotech’s first dose of the cell therapy. He experienced a lethal reaction as cytokine release syndrome hit, along with a grade 4 case of capillary leak syndrome. A separate study which also treated one patient is underway for acute myeloid leukemia.

The company’s stock was hammered by the bad news, dropping about 30% in pre-market trading and shedding more than $400 million of its market cap.

Significantly, neither of the first two patients treated with UCART123 experienced graft versus host disease, one of the chief fears involved in an allogeneic therapy that takes donated patient cells then adapts them into a ready-to-use therapy, bypassing a complex step required by the first CAR-Ts.

The FDA approved the first personalized CAR-T from Novartis just days ago, and Kite is expected to get an OK of its own soon. But the move by the FDA to slap a hold on these off-the-shelf therapies raises a host of thorny questions for Cellectis.

Juno $JUNO was also forced to halt a study of its lead CAR-T last year — one of the pioneering autologous versions that extracts patient cells and then adapts them before reinfusing them into patients — after patients died from cerebral edema. Then in an astonishingly short period of just a few days, regulators agreed to let researchers proceed with the pivotal trial after a questionable change-up in the preconditioning regimen used to prepare patients for the cell therapy. Almost immediately after treatment resumed, three more patients died followed by a trial halt and the subsequent decision to scrap a drug Juno and the FDA clearly didn’t completely understand.

Andre Choulika

Will that deadly mistake by regulators force them to be extra sensitive to this quick and early death in the UCART123 studies? Or will regulators be quick to green-light this new therapy back into the study, confident that years of treating CRS — a common reaction among patients receiving CAR-T therapy — can be managed?

Cellectis spelled out the downward spiral experienced by its first patient.

About a week ago, Cellectis reports, the data safety monitoring board suggested lowering the dose — to 6.25×104 UCART123 cells per kilogram — in both studies and capping cyclophosphamide to a total dose of 4g over three days. But the FDA followed up by demanding a halt to the BPDCN study along with the separate study on acute myeloid leukemia, which has also seen one patient treated. That patient experienced a grade 3 case of CRS and a grade 4 case of capillary leak syndrome — both of which resolved within a few days.

Capillary leak syndrome is a condition in which leaky blood vessels can cause a potentially lethal drop in blood pressure.

In the absence of any simple explanation, investors like Biren Amin at Jefferies speculated on causes and defects. His note:

We think there is a chance that CRS events could be mitigated upon lowering the dose of UCART123 beyond the DSMB recommendation and treating CRS symptoms more aggressively, although ultimately we look to more information. These events may be partially due to the UCART123 cells being from a healthy donor but, given the dearth of data, we think CLLS needs to approach through a more holistic approach and utlilizing key research on safety from autologous CAR-T trials over the last 3-4 years. However, we believe the Grd 3 infection (potentially a result of a neutropenic state) and Grd 4 CLS events have the potential to be target specific. For the latter, we note that sAEs involving CLS has been reported for Stemline’s (STML, NC) CD123-directed SL-401 therapeutic. It’s unclear if CLLS also required patients in their studies to have normal ejection fractions and certain pre-specified albumin levels at time of study entry.

Cellectis will get hammered by investors today, particularly as the enthusiasm for all things CAR-T seen in the past few days has swelled everyone’s stock price. Cellectis shares have soared past the $32 mark. The safety issue will challenge CEO André Choulika, a fierce and unabashed proponent of all things Cellectis.

“Cellectis is the first company doing CAR-T,” he told me during an interview at ASCO two years ago. “We are the first gene editing company in the world,” dating back to 1999. “There was no gene editing before us; we are the leaders.”

Today, Cellectis and Choulika will be leading a charge to resolve their biggest challenge to date. It won’t be easy.

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One week is not enough to rule out acute GvHD. Acute GvHD usually occurs within a month post allogeneic cells treatment. Chronic GvHD occurs mostly within a year.

Reply

Vanya ago↷

"Dumb" question: Did these CART-cells include an inducible apoptosis mechanism as a safety switch ( e.g. inducible caspase-9 suicide gene system) ? If yes, why did this fail ? I know, w^questions are the easy part...